Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

Christoph Muus; Malte D Luecken; Gokcen Eraslan; Avinash Waghray; Graham Heimberg; Lisa Sikkema; Yoshihiko Kobayashi; Eeshit Dhaval Vaishnav; Ayshwarya Subramanian; Christopher Smillie; Karthik Jagadeesh; Elizabeth Thu Duong; Evgenij Fiskin; Elena Torlai Triglia; Christophe Becavin; Meshal Ansari; Peiwen Cai; Brian Lin; Justin Buchanan; Sijia Chen; Jian Shu; Adam L Haber; Hattie Chung; Daniel T Montoro; Taylor Adams; Hananeh Aliee; Samuel J Allon; Zaneta Andrusivova; Ilias Angelidis; Orr Ashenberg; Kevin Bassler; Christophe Becavin; Inbal Benhar; Joseph Bergenstrahle; Ludvig Bergenstrahle; Liam Bolt; Emelie Braun; Linh T Bui; Mark Chaffin; Evgeny Chichelnitskiy; Joshua Chiou; Thomas M Conlon; Michael S Cuoco; Marie Deprez; David S Fischer; Astrid Gillich; Joshua Gould; Minzhe Guo; Austin J Gutierrez; Arun C Habermann; Tyler Harvey; Peng He; Xiaomeng Hou; Lijuan Hu; Alok Jaiswal; Peiyong Jiang; Theodoros Kapellos; Christin S Kuo; Ludvig Larsson; Michael A Leney-Greene; Kyungtae Lim; Monika Litvinukova; Ji Lu; Leif S Ludwig; Wendy Luo; Henrike Maatz; Elo Maddissoon; Lira Mamanova; Kasidet Manakongtreecheep; Charles-Hugo Marquette; Ian Mbano; Alexi M McAdams; Ross J Metzger; Ahmad N Nabhan; Sarah K Nyquist; Jose Ordovas-Montanes; Lolita Penland; Olivier B Poirion; Segio Poli; CanCan Qi; Daniel Reichart; Ivan Rosas; Jonas Schupp; Rahul Sinha; Rene V Sit; Kamil Slowikowski; Michal Slyper; Neal Smith; Alex Sountoulidis; Maximilian Strunz; Dawei Sun; Carlos Talavera-Lopez; Peng Tan; Jessica Tantivit; Kyle J Travaglini; Nathan R Tucker; Katherine Vernon; Marc H Wadsworth; Julia Waldman; Xiuting Wang; Wenjun Yan; Ali Onder Yildirim; William Zhao; Carly G K Ziegler; Aviv Regev

The gene programs of AT2 cells can also contribute to cross talk with alveolar macrophages. Our cell-cell interaction analysis suggests that AT2 cells engage with alveolar macrophages through Oncostatin M, CSF, IL1 and complement pathways, suggesting therapeutic hypotheses. The complement pathway is particularly intriguing in the context of COVID-19. First, viral protein glycosylation is a known trigger for the lectin pathway (LP) of the proteolytic complement . CC-BY-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.19.049254 doi: bioRxiv preprint cascade, such that in addition to classical complement activation via antibody complexes, other coronavirus glycoproteins can be recognized by LP-inducing host collectin proteins 154, 155 . Moreover, excessive complement activation resulting in acute lung injury and cytokine storms were also implicated in the pathogenesis of SARS 156 , and complement inhibition using the anti-C5 antibody eculizumab 157 is currently evaluated as anti-inflammatory experimental emergency treatment for severe COVID-19 in clinical trials (ClinicalTrials.gov identifier NCT04288713). In our analysis, multiple complement pathway proteases (e.g. C1R, C2, CFI) are co-expressed with ACE2 across different lung cell subsets (Fig. 6f,g, Extended Data Fig. 15 ) and complement inhibitory factor CD55 and complement protease C3 were preferentially expressed by ACE2 + TMPRSS2 + DPs within lung tissue, in multiciliated and secretory cells, respectively (Fig. 4a,c, Supplementary Table 6, Supplementary Tables 7,8) . Moreover, cell-cell interaction analysis predicted cross-talk between AT2 cells expressing complement proteins C3 and C5 and macrophages expressing cognate receptors. AT2 cell expression of negative complement regulators CFI and CD55 might represent a strategy for SARS-CoV-2 to at least partially escape complement surveillance.